Sleep-disordered breathing (SDB) affects at least 5% of the adult population (1) and is associated with hypertension (2), cardiovascular disease (3), and mortality (3- 4). Over the past 3 decades, relationships between SDB and cardiac arrhythmias have been explored (5- 10). Sleep-disordered breathing increases the risk of incident atrial fibrillation (11) and the risk of ventricular arrhythmias (12- 13), which may relate to the increased risk of sudden cardiac death (SCD) during overnight sleeping hours of persons with SDB (14). Proposed mechanisms to explain these relationships include the potentially pro-arrhythmic contributions of apnea-induced hypoxia and increased sympathetic nervous system activity, both acutely and in a tonic fashion (12,15- 17). However, a causal link between SDB and arrhythmia has not yet been established. Confirming a temporal relationship between SDB events and specific arrhythmia episodes could support causality and would have important implications for establishing therapeutic end points and refining cardiovascular risk stratification, as well as for elucidating the pathophysiology of arrhythmogenesis in SDB.

Recent data from SHHS (Sleep Heart Health Study) demonstrated a higher prevalence of atrial fibrillation (AF) and nonsustained ventricular tachycardia (NSVT) in patients with severe SDB (apnea-hypopnea index [AHI] ≥30 events/h) relative to patients with low levels of SDB (AHI <5 events/h); these effects persisted after adjusting for self-reported coronary heart disease (CHD) and CHD risk factors (10). However, this comparison of extremes of SDB did not address whether intermediate levels of SDB were also associated with arrhythmias, and inferences were limited by the cross-sectional design. Using the case-crossover design, an analytic approach developed to study the effects of transient exposures on the risk of acute events (18- 19), we now aim to extend prior research by investigating, across the full range of SDB, whether respiratory disturbances can trigger AF or NSVT.

All data were ascertained from the SHHS, a multicenter longitudinal study designed to investigate the cardiovascular consequences of SDB (20- 21). Of the 3,295 polysomnograms (PSGs) performed as part of the second SHHS examination, 2,816 records underwent detailed review of the electrocardiography channel with the aim of identifying studies with at least 1 episode of paroxysmal AF (PAF) or NSVT occurring during the sleep period. This sample consisted of all records with an AHI <30 events/h that were technically satisfactory (n = 2,569) and a sample of technically satisfactory studies (n = 247) with an AHI ≥30 events/h from subjects with body mass index between 18 and 40 kg/m² not on continuous positive airway pressure therapy who had been included in a prior study comparing arrhythmias across extreme levels of SDB (10). This approach identified 57 participants with PAF or NSVT.

Standardized questionnaires from the second SHHS examination conducted between 2001 and 2002 were used to collect demographic/anthropomorphic data (age, sex, race/ethnicity, height, weight), self-reported cardiovascular risk-factors/disease (hypertension, diabetes mellitus, smoking status, heart failure, history of CHD [defined as prior myocardial infarction or percutaneous/surgical revascularization], and arrhythmia-related data [use of antiarrhythmic drugs, prior pacemaker implantation]). The PSGs were performed and scored as described previously (10,21). The PSG summary data included total sleep time, AHI (the average number of apneas plus hypopneas per hour of sleep), sleep stage distributions, arousal index, average oxygen saturation during sleep, and percentage of sleep time spent at <90% oxygen saturation.

To investigate whether respiratory disturbances can trigger arrhythmic events, the case-crossover study design was applied (18- 19). This method analyzes the risk of an event occurring in the context of a transient exposure, with subjects serving as their own controls. For each case that is identified, a hazard period, during which subjects are presumed to be at increased risk for events, is examined for the presence of the exposure of interest. Correspondingly, referent (control) periods are also examined for the exposure of interest. Subjects serve as their own controls during periods when they are not having an event, and thus the association between the exposure and the event is not confounded by subject characteristics that remain essentially constant during the observation period (e.g., age, sex, body mass index, size of cardiac chambers). In the current study, the “events” are arrhythmias (PAF and NSVT), the “exposures” are respiratory disturbances (apneas or hypopneas), and the “referent” periods are derived from time spent in sinus rhythm (Figure 1).

We defined the hazard period as 90 s, which incorporates estimates of average respiratory disturbance duration (25 to 30 s), lag time between event cessation and nadir oxygen saturation (≈15 to 30 s), the delay between nadir oxygen saturation and resolution of hypoxia (≈10 to 15 s), and a short time after resolution of hypoxia during which its physiologic effects are still measurable (≈10 s). This sequence of events, as well as the duration of its components, is derived from SHHS data and from prior physiologic and clinical studies (15- 17,22- 26).

To identify referent periods for each arrhythmia, we selected randomly 3 epochs of sinus rhythm from the same subject that met the following criteria: 1) equal in duration to the hazard period (90 s); 2) same sleep stage (1, 2, 3 to 4, rapid eye movement [REM]) as the corresponding arrhythmic event; 3) <25% ectopic beats; and 4) absence of complex ventricular ectopy (bigeminy, trigeminy, quadrageminy, couplets (as defined in Mehra et al. [10]) and pauses >2 s. The strategy of matching on sleep stage was used to avoid confounding from state-dependent influences such as REM-related sympathetic nervous system surges. To minimize the effects of autocorrelation of exposure and the “carryover effect” (27), the referent periods were further restricted to those occurring at least 6 min (the duration of 4 hazard periods) before the onset of the arrhythmic event. Because it is unknown whether arrhythmias can affect the occurrence of respiratory disturbances, we used a unidirectional design; the hazard period and all referent periods were selected so that they occur before the arrhythmia of interest.

Electrocardiographic data were obtained from a single bipolar lead (lead I) sampled at 250 Hz collected as part of the overnight PSG. This channel was reviewed manually for arrhythmias using the CompuMedics EDF Studio viewer (CompuMedics, Abbotsford, Victoria, Australia). The channels that provide information on respiratory disturbances were disabled so that arrhythmias were identified without knowledge of surrounding respiratory status; these channels were also disabled during the referent period selection process. Episodes of NSVT, defined as ≥3 consecutive ventricular ectopic beats with an average heart rate of ≥100 beats/min, and PAF, defined as a period of irregular, narrow complex rhythm without evidence of organized atrial activity, were identified. Other recorded parameters included the absolute time of arrhythmia onset, duration of arrhythmia (the interval between its onset and the first QRS complex that appeared to be a normally conducted impulse originating at the sinus node), and the concurrent sleep stage. Most participants had a single arrhythmic event. However, 7 subjects had multiple arrhythmias over the course of their study. In these cases, 1 arrhythmia from each sleep state (non-rapid eye movement [NREM] or REM) was chosen at random and treated as an independent event in the analysis. Of these 7 subjects, 2 had all of their arrhythmias in NREM and thus contributed 1 event each, and 5 subjects had at least 1 arrhythmia in NREM and REM and therefore each contributed 2 events to the final dataset.

The primary exposure was a respiratory disturbance (apnea or hypopnea) defined solely by changes in amplitude of the airflow and effort signals for ≥10 s, as described previously (20- 21). For each arrhythmia, the associated hazard and referent periods were examined for respiratory disturbances. For each of those respiratory disturbances, the following characteristics were recorded: duration of the apnea or hypopnea, attendant nadir oxygen saturation (occurring within 25 s of the disturbance's termination), whether an electroencephalogram (EEG)-defined arousal occurred within 3 s of the disturbance's termination, and the interval between the onset of an associated arrhythmia (if present) and the termination of the respiratory disturbance. If any part of a respiratory disturbance occurred during a hazard or referent period, the subject was considered “exposed” during that period. For hazard and referent periods during which no respiratory disturbance occurred, the nadir oxygen saturation and the presence or absence of an EEG-defined arousal over the 90-s window were also recorded.

Secondary exposures included EEG-defined arousals and several definitions of hypoxia based on nadir oxygen saturation. We also created a 4-level variable to evaluate exposure to different levels of respiratory disturbance severity: 1) no respiratory disturbance (reference); 2) respiratory disturbances with neither an arousal nor hypoxia (defined as nadir SpO₂ ≤92%); 3) respiratory disturbances linked to a nadir SpO₂ ≤92%; and 4) respiratory disturbance linked to an EEG-defined arousal.

For quality control purposes, a randomly chosen subset (n = 10) of PSGs was examined independently by 2 investigators (K.M. and R.M.). For this subset, no interobserver differences were noted in arrhythmia detection or exposure classification of hazard/referent periods.

To provide context for the relative risk estimates derived from the case-crossover results, a crude absolute rate of arrhythmia associated with respiratory disturbances was estimated using data from the SHHS cohort. The rate of arrhythmia during the hazard period (R_h) was defined as the number of arrhythmias occurring during the hazard period (A_h) divided by the total exposure time (T_e):$Rh=AhTe$ The total exposure time (T_e) was calculated as the product of the total number of respiratory disturbances experienced by the entire cohort and the exposure time per respiratory disturbance (h):$Te=[∑i=1NAHIi×TSTi]×h$ where h is defined as the 90-s hazard period, N is the total number of participants in the cohort, and AHI_i and TST_i are the apnea-hypopnea index and the total sleep time, respectively, of a given participant. The rate of arrhythmia outside the hazard period (R_o) was defined as the number of arrhythmias occurring during nonexposed periods (A_o) divided by the total unexposed time (T_u):$Ro=AoTu$ The total unexposed time (T_u) was computed by subtracting the total exposed time (T_e) from the aggregate TST of the entire cohort:$Tu=(∑i=1NTSTi)−Te$ The absolute rate difference was taken as the difference between the rate of arrhythmia within the exposure period and the rate of arrhythmia outside of the exposure period (R_h − R_o). To make this absolute rate difference estimate more readily interpretable, we used the exposure period duration to convert the rate difference (excess arrhythmias per unit of sleep duration) to the number of respiratory disturbances associated with 1 excess arrhythmia (analogous to the “number needed to treat”). It should be noted that, unlike the matched odds ratio (OR) from the case-crossover design, this estimate has no inherent matching and therefore does not control for any confounding variables (demographics, medical history, and sleep characteristics).

Univariate descriptive statistics were used to summarize subject characteristics. Bivariate comparisons of characteristics for participants with and without arrhythmia were evaluated using the Pearson chi-square test for categorical data, the 2-sample t test for normally distributed measures, and the Wilcoxon rank-sum test for skewed measures. All subsequent analyses were restricted to the participants with arrhythmia. Descriptive analyses were stratified by type of arrhythmia (PAF or NSVT) and by period type (hazard or referent). To estimate the odds of an arrhythmia occurring during the hazard period after a respiratory disturbance relative to the odds of an arrhythmia occurring during normal nocturnal breathing, the Mantel-Haenszel matched OR and conditional logistic regression, stratified on the arrhythmia event, were used. For the 5 subjects who contributed 2 arrhythmias, each arrhythmia was treated as coming from an independent subject. The main analyses were repeated stratified on the individual and yielded similar results. Exploratory analyses were stratified by the type of arrhythmia (PAF or NSVT) and by sleep state (NREM vs. REM). We also examined the 2-way interaction between sleep state and the exposure to determine whether the OR for an arrhythmia varied by NREM/REM sleep state. Results are summarized using ORs and 95% confidence intervals (CIs); 2-sided p values are reported. Analyses were conducted using SAS version 9.1 (SAS Institute, Cary, North Carolina).

Demographic characteristics, relevant aspects of medical history, and selected PSG features of the cohort, stratified by arrhythmia status, are shown in (Table 1). The sample that demonstrated arrhythmias of interest (n = 57) was elderly (72.1 ± 10.1 years of age), predominantly Caucasian (77%), and just over one-half (56%) were male. Risk factors for heart disease were prevalent: nearly one-half (49%) had hypertension, 39% were obese, and 44% were active or former smokers. Eighteen percent of those with arrhythmia reported a history of CHD and 2 subjects reported a history of heart failure. Medication data were available for 52 participants; of these, 2 reported taking anti-arrhythmic drugs (1 each for class IB and class III), and 8 reported using beta-blockers. The TST by PSG was approximately 6 h, with just under 20% of that time spent in REM sleep (19.0 ± 6.3%). The median AHI was 13.6 events/h (interquartile range 6.2 to 25.5 events/h). Participants with arrhythmia were older, had a higher proportion of sleep time with SpO₂ <90%, and had slightly higher AHI compared with subjects who did not have arrhythmia. In addition, the arrhythmia group had an increased prevalence of hypertension, coronary heart disease, and high AHI (AHI ≥30 events/h) compared with the group without arrhythmia.

Features of the 62 detected arrhythmias are shown in (Table 2). The majority of reported arrhythmias were NSVT (76%) and approximately two-thirds (68%) of arrhythmias occurred in NREM sleep. Median arrhythmia duration was 7 s for PAF and 3 s for NSVT. The longest episode of PAF lasted nearly 5 min. The next longest episode was considerably shorter, at 12 s. The longest episode of VT lasted 35 s, with the next longest episode lasting 19 s.

A respiratory disturbance occurred in 44 of the 62 hazard periods (71%) and in 65 of the 186 referent periods (35%). The overall characteristics of respiratory events in the hazard and referent periods were similar; in both periods, the majority (77%) of respiratory events was hypopneas. Only 1 central apnea was identified, and it occurred in a referent period. Of the 44 respiratory events occurring in hazard periods, 18 (41%) occurred in REM sleep. Of the 65 respiratory events occurring in referent periods, 39 (60%) occurred in REM sleep. Respiratory disturbance duration, associated nadir oxygen saturation, and the proportion with EEG-defined arousals were similar for respiratory disturbances occurring in hazard and referent periods (data not shown).

(Table 3) shows the distribution of matched sets (1 hazard period and 3 control periods) according to the presence of a respiratory disturbance. Of the 62 sets, 27 sets were concordant on the exposure. Of those 27 concordant sets, 15 sets did not have a respiratory disturbance during the hazard period and, likewise, did not have a respiratory disturbance during any of the referent periods; 12 sets had a respiratory disturbance during the hazard period and also had respiratory disturbances during all 3 referent periods. The remaining 35 sets showed various levels of discordance on the exposure; for example, 5 sets had a respiratory disturbance during the hazard period, but only during 2 of the 3 referent periods. The odds of a nocturnal arrhythmia occurring within the 90-s hazard period after a respiratory disturbance was >17-fold greater than the odds of an arrhythmia occurring during normal nocturnal breathing (Mantel-Haenszel matched OR: 17.8; 95% CI: 5.0 to 63.0).

The conditional logistic regression results are shown in (Table 4) for the primary analysis and several exploratory analyses. The OR computed using conditional logistic regression was similar to the Mantel-Haenszel OR (17.5; 95% CI: 5.3 to 58.4). The results of the secondary analyses stratified by the subject, rather than by the arrhythmia event, were consistent with the primary finding. Analyses stratified by type of arrhythmia showed that the magnitude of the association for PAF and NSVT was similar to that for the overall group. An association remained for arrhythmias occurring during NREM sleep (OR: 14.2; 95% CI: 4.2 to 48.0), but could not be estimated for REM events because of the small number of discordant sets. However, there was no statistical evidence of an interaction between sleep stage and respiratory disturbance (p = 0.99).

Exploratory analyses examined the association between arrhythmias and secondary exposures. Significant associations between arrhythmias and respiratory disturbances were seen regardless of whether respiratory disturbances were associated with nadir SpO₂ ≤92% or arousal (Table 4). In contrast, when the exposure was defined as hypoxia or EEG-defined arousal regardless of the presence of a respiratory disturbance, the associations were weak, inconsistent, and not statistically significant (data not shown).

For the entire cohort of 2,816 participants, the rate of arrhythmia during exposed periods was 3.9/1,000 h sleep. The rate of arrhythmia during unexposed periods was 2.9/1,000 h sleep. Therefore, the absolute rate of arrhythmia associated with respiratory disturbances was estimated to be 1 excess arrhythmia per 1,000 h of sleep (with a median AHI of 23 events/h) or 1 excess arrhythmia per 40,000 respiratory disturbances. Thus, a person with moderate SDB (AHI of 30 events/h) who sleeps an average of 8 h per night would be estimated to have 1 excess arrhythmia every 5.6 months, or 2 per year.

The main finding of the present study is the nearly 18-fold increase in the relative risk of nocturnal arrhythmia within 90 s (a physiologically defined interval) after a respiratory disturbance in patients with a broad range of SDB severity. Prior clinical and epidemiologic studies have established an association between SDB and arrhythmia (5- 7,10,12- 13), but the temporal relationship between the two, particularly involving PAF and NSVT, has not previously been characterized. A small study in patients with central sleep apnea and heart failure demonstrated suppression of PVCs in the subset that responded to continuous positive airway pressure therapy (28), suggesting indirectly a link between central apneas and ventricular ectopy. A small study of patients with severely depressed left ventricular systolic function, severe SDB, and previously demonstrated ventricular ectopy on Holter monitoring demonstrated that PVCs occurred more frequently in the apneic phase of obstructive apneas than during other phases of the respiratory cycle (29). Another study showed a higher frequency of apnea-associated compared with non–apnea-associated arrhythmias in 8 patients with SDB, left ventricular dysfunction, and prior implantable cardioverter-defibrillator device placement (13). However, none of these studies quantified the extent to which sleep-related respiratory disturbances operated as triggers for arrhythmias, and none investigated PAF as an arrhythmia of interest.

A prior study from the SHHS reported an increased odds of arrhythmias among subjects with severe SDB (AHI ≥30 events/h) compared with subjects who had an AHI of <5 events/h (10). However, that analysis did not address the propensity for arrhythmias in subjects with more moderate levels of SDB, as is found more frequently in the general population. The current report analyzed all records of participants with an AHI <30 events/h. The majority of identified arrhythmias occurred among those with only moderate levels of SDB (AHI 5 to 30 events/h). As shown by the moderate median AHI of our cohort and the finding that most of the respiratory disturbances preceding arrhythmias were hypopneas (as opposed to apneas), neither the severity of SDB nor the severity of individual respiratory disturbances needs to be extreme to increase the risk of arrhythmia.

In this study, we attempted to identify the relative contributions of hypoxia and arousal to arrhythmogenesis. We identified all respiratory disturbances solely on the basis of changes in airflow and effort signal amplitude, without requiring a linked desaturation or arousal. We then secondarily assessed whether the extent of linked desaturation or arousal was related to propensity for PAF or NSVT. In these analyses, the ORs for arrhythmia did not vary according to whether nadir saturation levels fell below 92% nor did they vary according to whether respiratory disturbances were associated with a cortical arousal. However, since more than one-half of the respiratory disturbances in the hazard/referent periods were associated with a desaturation of ≥3% (a commonly used clinical criterion) and the mean desaturation for all respiratory disturbances that occurred in hazard/referent periods was ≈4%, it is possible that some degree of hypoxic stress was contributory to the observed associations. The overall small number of respiratory disturbances may have limited the ability to discern effects associated with arousal or desaturation. Nonetheless, our data also raise the possibility that additional mechanisms, such as large changes in intrathoracic pressure and stimulation of baroreflexes, may contribute to the link between respiratory disturbances and arrhythmias (25).

In interpreting our findings, it is important to distinguish between relative and absolute risk. The overall frequency of arrhythmias in this community-based cohort was very low while the frequency of respiratory disturbances was moderate. Crude estimates of absolute arrhythmia rate suggest that 1 excess arrhythmia may occur per 1,000 h of sleep in subjects with a median AHI of 23 events/h. The high and growing prevalence of SDB, which influences the effective hazard period in the population, suggests that respiratory disturbances may contribute to a considerable number of excess episodes of PAF or NSVT. In addition, it is possible that risk is not evenly distributed in the population and that the rate of SDB-associated arrhythmias may be even higher among patients with impaired cardiac function or with other risk factors that enhance their vulnerability to physiological stressors.

The high relative risk may provide insights into prior studies demonstrating adverse cardiovascular outcomes in patients with SDB, including AF. Our results reveal a significant association between the risk of PAF and the presence of a respiratory disturbance within the pre-defined hazard period. Significant associations between AF and SDB have been previously reported (9,30); specifically, SDB is a risk factor for incident AF (11) and for recurrence of AF after electrical cardioversion (31). Repeated exposures to intervals of relatively high risk for PAF, both within a given night and over many nights, may result in an increasing cumulative burden of discrete PAF episodes over time. Each of these paroxysms may increase the propensity for further and sustained episodes of AF due to electrical remodeling within the atria (32). Therefore, untreated SDB may serve as an ongoing source of AF stimulation, leading ultimately to initiation or recurrence of clinically significant arrhythmia. Correspondingly, it is plausible that treatment of underlying SDB may inhibit progression of subclinical PAF to a more detrimental form of the arrhythmia. A marked rise in the prevalence of AF is anticipated in coming years, with ≈60% of that increase estimated to be attributable to obesity (33). Our data, which temporally link SDB events and the risk of PAF, suggest that unrecognized SDB may be a contributing factor to the projected increase in AF due to obesity.

Our finding of increased risk of NSVT during the hazard period after a respiratory disturbance may provide further insight into the observed nocturnal predominance of sudden cardiac death in SDB patients (14). For patients with structural heart disease, the risk of SCD is higher for those with NSVT relative to those without it (34- 35). Therefore, our findings raise the possibility that, in a sufficiently susceptible population, SDB increases the nocturnal risk of SCD by providing frequent nocturnal exposure to a stimulus that increases the likelihood of ventricular arrhythmia. This possibility is supported by a recent study of heart failure patients with implantable cardioverter-defibrillator devices that demonstrated that appropriate antitachycardia therapies for ventricular tachycardia or ventricular fibrillation were delivered more frequently in those with SDB than in those without SDB; this relationship was present only during sleeping hours (36). Furthermore, even in the absence of structural heart disease, SDB has been found to be highly prevalent in patients with frequent premature ventricular contractions and/or ventricular tachycardia (37); our results are consistent with this observation as well.

A strength of the present study was the utilization of the case-crossover design. Because subjects served as their own controls, this approach essentially eliminated confounding by subject characteristics that remained constant during the observation period, a challenge in all prior work in this area. In addition, the study participants are part of a community-based cohort, rather than patients with a homogenous cardiovascular profile, and represent the full spectrum of SDB severity; both of these features enhance the generalizability of our findings.

A limitation of the current study is the small number of detected arrhythmias (38), which reduced the ability to detect potential effect modification by underlying risk factors, subject characteristics, and sleep-state effects. However, the case-crossover design allows for analytic efficiency as well as a minimum of confounding for between-individual comparisons. Detailed information regarding daytime arrhythmia prevalence and temporal distribution are not readily available, rendering impractical a direct comparison between the arrhythmia profiles of our cohort during wakefulness and sleep. We limited our assessment of nocturnal arrhythmias to PAF and NSVT; inclusion of complex ventricular ectopy as part of the analysis would have increased our sample size, perhaps at the expense of direct clinical impact of the results.

This study demonstrates that, across the range of SDB, the risk of clinically important nocturnal arrhythmias is markedly increased shortly after the occurrence of apneas and hypopneas during sleep. This work provides further evidence that intermittent airflow obstruction may lead to clinically important adverse cardiac effects, and that such effects may occur even in persons without severe levels of SDB. Further research is needed to evaluate the ability of pharmacotherapy and/or SDB treatment to modify these associations.